Abnormal network activity in a targeted genetic model of human double cortex

Area of Science:

• Neuroscience
• Developmental Biology
• Epileptology

Background:

• Mutations in Doublecortin (DCX) cause severe neurological disorders in humans, including mental retardation and infantile epilepsies.
• The precise mechanisms underlying these conditions remain poorly understood.
• Existing mouse models (DCX-/-) lack relevant neocortical abnormalities, limiting their utility.

Purpose of the Study:

• To investigate the neuronal and network properties of ectopic neurons and overlying cortical neurons in a rodent model of DCX-related cortical dysplasia.
• To elucidate how aberrant neuronal migration impacts cortical activity and contributes to dysfunction.

Main Methods:

• In utero knockdown of DCX RNA to create a cortical band heterotopia model in rodents.
• Dynamic calcium imaging, anatomical analysis, and electrophysiological recordings.
• Comparison of ectopic, overlying, and control neurons.

Main Results:

• Ectopic neurons exhibited abnormal subcortical projections and delayed maturation of GABAergic signaling.
• Overlying cortical neurons showed increased glutamatergic synaptic currents, indicating reactive plasticity.
• Both ectopic and overlying neurons displayed enhanced coactivity and synchronized network oscillations, including during evoked epileptiform bursts.

Conclusions:

• Neuronal migration disorders significantly alter not only the misplaced neurons but also their target cortical areas.
• This dual impact on neuronal migration and cortical organization is proposed as a key factor in the pathophysiology of DCX-related brain dysfunction.